• A controlled three-month prospective collaborative investigation involving eight National Institute on Drug Abusesupported polydrug units was carried out. Clinical review of test protocols assessed 37% of polydrug users, 26% of psychiatric patients, and 8% of nonpatients as impaired on the Halstead-Reitan Battery. Impairment in test performance was related to increasing age, educational deprivation, and premorbid medical factors in all groups, extensive use of CNS depressants and opiates among polydrug users, and extensive use of antipsychotic drugs in psychiatric patients. Both language-related and perceptuomotor neuropsychological test deficits were found in polydrug users, but only the latter in psychiatric patients. At three-month follow-up 34% of polydrug users, 27% of psychiatric patients, and 4% of nonpatients were impaired in these test performances. Recent drug-taking (polydrug group) and schizophrenia diagnosis (psychiatric patients) were additional correlates of test impairment. Persistence of performance deficit in polydrug users raises the possibility that CNS depressants and opiates may have longer-term, slowly reversible, or even permanent effects on neuropsychological tests. The same possibility exists for antipsychotic drugs. The link of these test deficits to other specific neuropsychological functions, to performance in life situations generally, or to specific brain dysfunction, as well as the basis for a lack of test impairments in the majority of polydrug subjects remain to be determined.